N-(D-.alpha.-methyl-.beta.-mercaptopropionyl)-L-proline (4) has potent angiotensin converting enzyme inhibiting activity and is an antihypertensive agent generically called captopril (erg. Biochemistry, 16, 5487 (1977)).
Various methods are known for the production of N-(D-.alpha.-methyl-.beta.-mercaptopropionyl)-L-proline (4) (hereinafter also called captopril). For instance, in Japanese Kokoku Publication Sho-60-56705, Japanese Kokai Publication Hei-5-17435 and Japanese Kokai Publication Hei-5-221966 and elsewhere, there are disclosed processes for producing captopril which comprises deriving an N-(D-.alpha.-methyl-.beta.-acylthiopropionyl)-L-proline (3) from a D-.alpha.-methyl-.beta.-acylthiopropionic acid halide or DL-.alpha.-methyl-.beta.-acylthiopropionic acid halide and L-proline by utilizing the Schotten-Baumann reaction and then subjecting the intermediate (3) to deacylation.
While the medical and medicinal expenses are on a growing trend, captopril is expectedly one of large-sale generic drugs and it is of great significance to develop a process for producing high-purity captopril at low cost and in easy and simple manner.
As for the specifications of captopril, the Japanese Pharmaceutical Index requires that the captopril bulk substance contains not less than 97.5% of captopril and has a melting point of 105.degree. C. to 110.degree. C. and that the content of captopril disulfide, which is one of related substances (organic impurities), is not more than 2.5%, among others. The U.S. Pharmacopeia requires, among others, that the content of .beta.-mercapto-.alpha.-methylpropionic acid as a related substance (organic impurity) is not more than 0.1%. In view of the nature of a medicine ingredient, it is needless to say that said bulk substance can hardly contain other related substances or organic impurities not referred to in such specifications or, in other words, it is strongly desired that their contents do not exceed 0.1%.
Concerning the quality of captopril products obtained by subjecting the above-mentioned acid halide and L-proline to Schotten-Baumann reaction, followed by deacylation, the impurities possibly contained therein and the methods of preventing the formation thereof, literature references disclose, for example, as follows:
In the above-cited Japanese Kokai Publication Hei-5-221966, it is described that N-.alpha.-methyl-.beta.-methyl-.beta.-hydroxycarbonyl)ethylthiopropionyl! -L-proline of the formula (7) given below, or N-acetyl-L-proline, among others, is formed as a by-product in the Schotten-Baumann reaction. ##STR4##
According to the teaching disclosed in said Japanese Kokai Publication Hei-5-221966, however, the Schotten-Baumann reaction and the subsequent deacylation are carried out in a continuous manner, so that it is not very certain in which step the above-mentioned by-products are formed as impurities. For preventing the formation of these products according to said teaching, the pH, temperature and D-.alpha.-methyl-.beta.-acylthiopropionic acid halide/L-proline mole ratio, among others, are important in carrying out the Schotten-Baumann reaction. As optimal values, there are mentioned an initial pH of 9.9 to 10.1, a final pH of 10.9 to 11.0, a reaction temperature of not higher than 10.degree. C., and a D-.alpha.-methyl-.beta.-acylthiopropionic acid halide/L-proline mole ratio of 1.0 to 1.1.
In U.S. Pat. No. 5,387,697, it is disclosed that the compound of the formula (8) ##STR5## is formed as a by-product during the Schotten-Baumann reaction and it is described that for preventing the formation of this impurity, the Schotten-Baumann reaction should be carried out at 0.degree. C. to 5.degree. C. in 0.25 M potassium phosphate buffer solution, while adjusting the pH to 7.5 to 8.5 with potassium hydroxide. However, in said patent specification, no mention is made of N-.alpha.-methyl-.beta.-(.beta.-methyl-.beta.-hydroxycarbonyl)-ethylthiop ropionyl!-L-proline (7) and no reference is made to the relation between the compound (7) and the compound of the above formula (8).
As regards the reaction conditions to be employed for preventing the formation of the compound of formula (8), which is a precursor of the compound of formula (7), in the Schotten-Baumann reaction, those described in U.S. Pat. No. 5,387,697 Specification constitute the only prior art, which, however, has the following problems: for instance, the use of the phosphate produces a problem in waste water treatment because of its eutrophication potential, the pH adjustment by adding potassium hydroxide during reaction makes the procedure complicated, and the formation of the compound of formula (8) can be prevented only to an unsatisfactory extent.
Japanese Kokai Publication Hei-7-10835 discloses a process for purifying captopril which comprises treating an acyl-protected captopril intermediate of the formula (3) given above with active carbon and radiolite in an organic solvent to thereby eliminate the disulfide represented by the formula (9) given below, which otherwise possibly gets into the product captopril. ##STR6##
However, there is no mention whatever of the efficiency of the elimination of by-products of the formula (5) shown below and the by-product of the formula (6) shown below. In the formulas, n represents an integer of 2 to 4 and R.sub.1 represents an acyl group. ##STR7##
Check experiments performed by the present inventors showed that the above-mentioned treatment with active carbon etc. in organic solvents can hardly be expected to be effective in eliminating the by-products represented by the above general formula (5) or formula (6).
U.S. Pat. No. 5,387,697, CN Patent Publication 1,051,909 and CN Patent Publication 1,034,920, for instance, respectively describe the crystallization of the acyl-protected captopril intermediate of the above formula (3) from an aqueous solution thereof. In each case, the crystallization is effected at room temperature or a temperature therebelow and there is no mention whatever of the efficiency of the elimination of the by-products represented by the above general formula (5) or formula (6). Check experiments made by the present inventors, however, revealed that these methods can hardly be expected to be effective in removing the by-products represented by the above general formula (5) and the by-product represented by formula (6).
Thus, so far, neither a process for producing captopril or its acylated intermediate by which the by-product formation can be prevented nor a method of purification by which by-products can be removed from captopril or its acyl-protected intermediate contaminated therewith has been available.
As detailedly described hereinabove, the prior art captopril products obtained by the Schotten-Baumann reaction between the above-mentioned acid halide and L-proline and the subsequent deacylation are contaminated with various impurities and it is very difficult to obtain high-quality captopril.